5,7-Dimethoxycoumarin ameliorates vincristine induced neuropathic pain: potential role of 5HT3 receptors and monoamines.

Vincristine is the drug of choice for Hodgkin's lymphoma, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Despite its significant anticancer effects, it causes dose-dependent neuropathy, leading to compulsive dose reduction. The available drugs used for vincristine-induced neuropathic pain (VINP) have a range of safety, efficacy, and tolerability issues prompting a search for new therapies. 5,7-Dimethoxycoumarin (5,7-DMC) also known as citropten, is a natural coumarin found in the essential oils of citrus plants such as lime, lemons, and bergamots, and it possesses both antidepressant and anti-inflammatory effects. This study was designed to investigate the possible analgesic and antiallodynic effects of 5,7-DMC in a murine model of VINP. Vincristine was administered to groups of BALB/c male mice (0.1 mg/kg intraperitoneally) once daily for 14 days to induce VINP. Thermal hyperalgesia and mechanical allodynia were quantified using the tail immersion test and von Frey filament application method. The levels of monoamine neurotransmitters and vitamin C in frontal cortical, striatal and hippocampal tissues, as well as the TNF-α level in plasma, were quantified using high performance liquid chromatography and ELISA respectively. On day 15 of the protocol, acute treatment with 5,7-DMC clearly reversed VINP thermal hyperalgesia, mechanical static allodynia, mechanical dynamic allodynia, and cold allodynia. The activity of 5,7-DMC against hyperalgesia and allodynia was inhibited by pretreatment with ondansetron but not naloxone, implicating a 5-HT3 receptor involvement. VINP vitamin C levels were restored by 5,7-DMC in the frontal cortex, and changes in serotonin, dopamine, adenosine, inosine and hypoxanthine levels caused by vincristine were reversed either fully or partially. Additionally, the vincristine-induced rise in hippocampal serotonin, dopamine, inosine and striatal serotonin was appreciably reversed by 5,7-DMC. 5,7-DMC also reversed the vincristine-induced increase in the plasma level of TNF-α. In negating the changes in the levels of some neurotransmitters in the brain caused by vincristine, 5,7-DMC showed stronger effects than gabapentin. It was concluded that, there is a potential role of 5-HT3 receptors and monoamines in the amelioration of VINP induced by 5,7-DMC, and the use of this compound warrants further investigation.

Diosgenin normalization of disrupted behavioral and central neurochemical activity after single prolonged stress.

Introduction: Post-traumatic stress disorder (PTSD) is a chronic mental illness triggered by traumatic experiences such as wars, natural disasters, or catastrophes, and it is characterized by anxiety, depression and cognitive impairment. Diosgenin is a steroidal sapogenin with known neuroprotective and antioxidant properties. This study aimed to assess the pharmacological potential of diosgenin in a single prolonged stress (SPS) model of PTSD, plus other behavioral models along with any consequent alterations in brain neurochemistry in male mice. Methodology: SPS was induced by restraining animals for 2 h, followed by 20 min of forced swim, recuperation for 15 min, and finally, exposure to ether to induce anesthesia. The SPS-exposed animals were treated with diosgenin (20, 40, and 60 mg/kg) and compared with the positive controls, fluoxetine or donepezil, then they were observed for any changes in anxiety/depression-like behaviors, and cognitive impairment. After behavioral screening, postmortem serotonin, noradrenaline, dopamine, vitamin C, adenosine and its metabolites inosine and hypoxanthine were quantified in the frontal cortex, hippocampus, and striatum by high-performance liquid chromatography. Additionally, animal serum was screened for changes in corticosterone levels. Results: The results showed that diosgenin reversed anxiety- and depression-like behaviors, and ameliorated cognitive impairment in a dose-dependent manner. Additionally, diosgenin restored monoamine and vitamin C levels dose-dependently and modulated adenosine and its metabolites in the brain regions. Diosgenin also reinstated otherwise increased serum corticosterone levels in SPS mice. Conclusion: The findings suggest that diosgenin may be a potential candidate for improving symptoms of PTSD.

Enhancing Radiation Safety Culture: Investigating the Mediating Role of Awareness Among Orthopedic Doctors and Operation Theatre Assistants.

INTRODUCTION: The increasing use of minimally invasive orthopedic procedures has led to a greater reliance on fluoroscopy, resulting in elevated radiation exposure for surgeons. This study aimed to evaluate the knowledge, awareness, and daily practices of orthopedic surgeons regarding radiation safety in an academic hospital. Understanding radiation safety is crucial to minimize patient exposure and prevent adverse effects on surgeons. METHODS: This cross-sectional study was conducted at the Department of Orthopedics of different tertiary care hospitals in Rawalpindi, Pakistan. Data were collected prospectively for two years, and a total of 505 participants, including residents, consultants, and operation theatre assistants, completed a questionnaire. The questionnaire was validated by experts and covered information on fluoroscopy usage, frequency of surgeries, awareness of radiation safety, and protective measures. Ethical approval was obtained, and data were analyzed using SPSS version 26.0. RESULTS: The majority of participants were male (74.1%), and the sample included various ranks of orthopedic surgeons. Only 56.2% of participants were aware of the usage of fluoroscopy, and 40.2% had read some research on the topic. While 44.6% used lead aprons for radiation protection, the usage of other protective measures and dosimeters was limited. The mediation analysis showed an insignificant indirect association between the rank of orthopedic surgeons, number of surgeries performed, and fluoroscopy usage as a mediator. Awareness and reading research on fluoroscopy were significantly associated with radiation protection. CONCLUSION: The knowledge, awareness, and daily practices of orthopedic surgeons regarding radiation safety in fluoroscopy use need improvement. The findings emphasize the importance of implementing training programs, providing radiation protection devices, and ensuring compliance with safety guidelines.

The relationship between knowledge, attitude, and practice of plasma donation with age and gender as moderators: a cross-sectional survey.

Convalescent plasma therapy has gained worldwide notoriety since its inception as a form of soul treatment for terminally ill patients. This study investigates the link between knowledge, attitude, and practice of plasma donation while simultaneously probing the moderative role of age and gender in this context. Method: A cross-sectional study was undertaken in Rawalpindi, Pakistan, on COVID-19-recovered patients (coronavirus disease 2019). In all, 383 persons were chosen using simple random sampling. A prestructured questionnaire was first validated and then used as a tool for data collection. jMetrik version 4.1.1 and SPSS version 26 were used to enter and analyze the data. Reliability analysis, hierarchal regression, and logistic regression analysis were applied. Results: A total of 85.1% and 58.2% of 383 individuals had a favorable attitude and sufficient knowledge toward plasma donation, respectively. Plasma donation was observed in 109 (28.5%) of the individuals. Plasma donation practice was shown to be strongly related to plasma donation attitude [adjusted odds ratio (AOR)=4.48; P<0.05] and knowledge (AOR=3.78; P<0.001). Females who had more plasma donation knowledge and attitude tend to donate more compared to males. However, no interactional effect of gender×knowledge and attitude, and age×knowledge and attitude was found with plasma donation practice. Conclusion: Plasma donation was uncommon, even though the majority of individuals had a good mindset and were well-informed. Fear of getting a health problem was linked to the decreased practice.

The Effect of Dexamethasone on Postoperative Pain Management in Patients Undergoing Total Knee Arthroplasty: A Randomized Controlled Trial.

Objective The objective of this study was to evaluate the effectiveness of dexamethasone in treating postoperative pain in patients undergoing total knee arthroplasty (TKA). Methodology This randomized controlled trial (RCT) was completed over the course of two years (September 7, 2015, to September 6, 2017). In the course of their treatment for osteoarthritis of the knee, all of the patients who had primary unilateral total knee replacement (TKR) participated in the research. Under spinal anesthesia, each patient had medial para-patellar approach medial orthopedic surgery. Patients were assigned to group A or group B based on a random selection. Each of the groups consisted of 79 individuals. Group A was given dexamethasone through intravenous administration at a dose of 0.1 mg/kg before the operation. During the subsequent period of 24 hours, no more treatment was administered (control group). On a predesigned questionnaire, postoperative pain was measured using the visual analog scale (VAS) for pain. Functional results, duration of hospital stay, and complications were all recorded on the questionnaire (VAS). Analysis of data was carried out using the Statistical Package for the Social Sciences (SPSS) version 23 (IBM SPSS Statistics, Armonk, NY, USA). Results There were 158 patients in total in the study, out of which 98 were females and 60 were males in the group. The patients' average body mass index (BMI) was 26.94 ± 3.14 kg/m2. Patients in group A had lower postoperative analgesic and antiemetic needs and higher VAS scores and spent less time in the hospital than patients in group B. There were no postoperative problems in either group. Conclusion In patients undergoing TKA, the use of dexamethasone during and after surgery decreases pain, the need for analgesics, and the duration of hospital stay.

Effect of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide on cognitive deficits and hippocampal plasticity during nicotine withdrawal in rats.

Withdrawal from chronic nicotine has damaging effects on a variety of learning and memory tasks. Various Sulfonamides that act as carbonic anhydrase inhibitors have documented role in modulation of various cognitive, learning, and memory processing. We investigated the effects of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS) on nicotine withdrawal impairments in rats using Morris water maze (MWM), Novel object recognition, Passive avoidance, and open field tasks. Also, Brain-derived neurotrophic factor (BDNF) profiling and in vivo field potential recording were assessed. Rats were exposed to saline or chronic nicotine 3.8 mg/kg subcutaneously for 14 days in four divided doses, spontaneous nicotine withdrawal was induced by quitting nicotine for 72 h (hrs). Animals received 4-FBS at 20, 40, and 60 mg/kg after 72 h of withdrawal in various behavioral and electrophysiological paradigms. Nicotine withdrawal causes a deficit in learning and long-term memory in the MWM task. No significant difference was found in novel object recognition tasks among all groups while in passive avoidance task nicotine withdrawal resulted in a deficit of hippocampus-dependent fear learning. Anxiety like behavior was observed during nicotine withdrawal. Plasma BDNF level was reduced during nicotine withdrawal as compared to the saline group reflecting mild cognitive impairment, stress, and depression. Withdrawal from chronic nicotine altered hippocampal plasticity, caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results showed that 4-FBS at 40 and 60 mg/kg significantly prevented nicotine withdrawal-induced cognitive deficits in behavioral as well as electrophysiological studies. 4-FBS at 60 mg/kg upsurge nicotine withdrawal-induced decrease in plasma BDNF. We conclude that 4-FBS at 40 and 60 mg /kg effectively prevented chronic nicotine withdrawal-induced impairment in long term potentiation and cognitive performance.

Analgesic and Antiallodynic Effects of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide in a Murine Model of Pain.

INTRODUCTION: Physical, chemical, thermal injuries along with infectious diseases lead to acute pain with associated inflammation, being the primary cause of hospital visits. Moreover, neuropathic pain associated with diabetes is a serious chronic disease leading to high morbidity and poor quality of life. OBJECTIVE: Earlier multiple sulphonamides have been reported to have an antinociceptive and antiallodynic profile. 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS), a synthetic sulfonamide with reported carbonic anhydrase inhibitory activity, was investigated for its potential effects in mice model of acute and diabetic neuropathic pain. METHODS AND RESULTS: 4-FBS was given orally (p.o.) one hour before the test and then mice were screened for antinociceptive activity by using the tail immersion test, which showed significant antinociceptive effect at both 20 and 40 mg/kg doses. To explore the possible mechanisms, thermal analgesia of 4-FBS was reversed by the 5HT3 antagonist ondansetron 1mg/kg intraperitoneally (i.p.) and by the µ receptor antagonist naloxone (1 mg/kg i.p.), implying possible involvement of serotonergic and opioidergic pathways in the analgesic effect of 4-FBS. Diabetes was induced in mice by a single dose of streptozotocin (STZ) 200 mg/kg i.p. After two weeks, animals first became hyperalgesic and progressively allodynic in the fourth week, which was evaluated through behavioral parameters like thermal and mechanical tests. 4-FBS at 20 and 40 mg/kg p.o. significantly reversed diabetes-induced hyperalgesia and allodynia at 30, 60, 90, and 120 minutes. CONCLUSION: These findings are significant and promising while further studies are warranted to explore the exact molecular mechanism and the potential of 4-FBS in diabetic neuropathic pain.

Effect of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide on Acquisition and Expression of Nicotine-Induced Behavioral Sensitization and Striatal Adenosine Levels.

INTRODUCTION: Behavioral sensitization is a phenomenon that develops from intermittent exposure to nicotine and other psychostimulants, which often leads to heightened locomotor activity and then relapse. Sulfonamides that act as carbonic anhydrase inhibitors have a documented role in enhancing dopaminergic tone and normalizing neuroplasticity by stabilizing glutamate release. OBJECTIVE: The aim of the current study was to explore synthetic sulfonamides derivative 4-fluoro-N-(4-sulfamoylbenzyl) benzene-sulfonamide (4-FBS) (with documented carbonic anhydrase inhibitory activity) on acquisition and expression of nicotine-induced behavioral sensitization. METHODS: In the acquisition phase, selected 5 groups of mice were exposed to saline or nicotine 0.5mg/kg intraperitoneal (i.p) for 7 consecutive days. Selected 3 groups were administered with 4-FBS 20, 40, and 60 mg/kg p.o. along with nicotine. After 3 days of the drug-free period, ie, day 11, a challenge dose of nicotine was injected to all groups except saline and locomotor activity was recorded for 30 minutes. In the expression phase, mice were exposed to saline and nicotine only 0.5 mg/kg i.p for 7 consecutive days. After 3 days of the drug-free period, ie, day 11, 4-FBS at 20, 40, and 60 mg/kg were administered to the selected groups, one hour after drug a nicotine challenge dose was administered, and locomotion was recorded. At the end of behavioral experiments, all animals were decapitated and the striatum was excised and screened for changes in adenosine levels, using HPLC-UV. RESULTS: Taken together, our findings showed that 4-FBS in all 3 doses, in both sets of experiments significantly attenuated nicotine-induced behavioral sensitization in mice. Additionally, 4-FBS at 60mg/kg significantly lowered the adenosine level in the striatum. CONCLUSION: The behavioral and adenosine modulation is promising, and more receptors level studies are warranted to explore the exact mechanism of action of 4-FBS.

Antinociceptive effectiveness of Tithonia tubaeformis in a vincristine model of chemotherapy-induced painful neuropathy in mice.

BACKGROUND: Chemotherapy induced peripheral neuropathy (CIPN) is a painful side-effect of commonly used chemotherapeutic agents that profoundly impair the quality of life of patients as the current pharmacotherapeutic strategies are inefficient in providing adequate pain relief. Complementary and alternative medicine (CAM) therapies are preferred by patients with neuropathic pain as they experience insufficient control of pain with conventional medications. This study describes the antinociceptive effect of Tithonia tubaeformis (Jacq.) Cass. in a vincristine mouse model of established CIPN. METHODS: Tithonia tubaeformis hydromethanolic extract was tested for preliminary qualitative phytochemical analysis and acute oral toxicity test in mice. The antinociceptive effect was investigated using the abdominal constriction (writhing) and tail immersion tests (25-200 mg/kg). The anti-neuropathic effect was determined in the vincristine mouse model, established by daily administration of vincristine (0.1 mg/kg/day, i.p) for consecutive 14 days. Acute treatment with Tithonia tubaeformis (100 and 200 mg/kg) and the positive control, gabapentin (75 mg/kg) was carried out on the 15th day of the last vincrsitine dose and the animals were tested for allodynia and thermal hyperalgesia at 30-120 min post extract/drug administration. RESULTS: Vincristine produced significant temporal tactile allodynia and thermal hyperalgesia (P < 0.01 and P < 0.001 on day 7 and 14) and was maintained for the subsequent day (P < 0.001 during 30-120 min). Tithonia tubaeformis was effective in attenuating the vincristine-induced allodynia and thermal hyperalgesia at 100 mg/kg (P < 0.05, P < 0.01) and 200 mg/kg (P < 0.01, P < 0.001). Similarly, gabapentin also showed a robust antinociceptive effect in counteracting the vincristine associated behavioral alterations. CONCLUSIONS: Tithonia tubaeformis can be an effective CAM therapeutic remedy for established CIPN due to its potential antinociceptive effect in attenuating vincristine-induced neuropathy.

Medicinal plants of the genus Anthocleista--A review of their ethnobotany, phytochemistry and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Anthocleista of the Gentianaceae family contains 14 species of trees and shrub-like plants distributed in tropical Africa, in Madagascar and on the Comoros. Traditionally, they are commonly used in the treatment of diabetes, hypertension, malaria, typhoid fever, obesity, diarrhea, dysentery, hyperprolactinemia, abdominal pain, ulcer, jaundice, asthma, hemorrhoids, hernia, cancer, wounds, chest pains, inflammations, rheumatism, STDs, infertility and skin diseases. They serve as an anthelmintic, laxative, diuretic and contraceptive. This review aims to provide for the first time a repository of ethnopharmacological information while critically evaluating the relation between the traditional medicinal uses, chemical constituents and pharmacological activities of the Anthocleista species so as to unveil opportunities for future research. MATERIALS AND METHODS: A search for relevant information on Anthocleista species was performed on scientific databases (Pubmed, Google Scholar, SciFinder, Web of Science, Scopus, PubChem and other web sources such as The Plant List, Kew Botanical Garden and PROTA) and books, PhD and MSc dissertations for un-published resources. RESULTS: Out of the 14 species of Anthocleista, 6 have been reported in literature to be widely used in traditional medicine for the treatment of various ailments. The six species include: A. djalonensis, A. vogelii, A. nobilis, A. grandiflora, A. schweinfurthii, and A. liebrechtsiana. The chemical compounds isolated from Anthocleista species fall into the class of phytochemicals such as secoiridoids, nor-secoiridoids, xanthones, phytosterols, triterpenes, alkaloids, and others of which majority of the compounds were isolated from A. djalonensis and A. vogelii. The in vitro and in vivo pharmacological studies on the crude extracts, fractions and few isolated compounds of Anthocleista species showed antidiabetic, antiplasmodial, antimicrobial, hypotensive, spasmogenic, anti-obesity, antiulcerogenic, analgesic, anti-inflammatory, antioxidant, antitrypanosomal, anthelmintic, fertility, diuretic and laxative activities which supports most of their uses in traditional medicine. However, the bulk of the studies where centered on the antidiabetic, antiplasmodial and antimicrobial activities of Anthocleista species, although the evidence of its antiplasmodial effect was not convincing enough due to the discrepancies between the in vitro and in vivo results. CONCLUSION: A. djalonensis and A. vogelii are potential antidiabetic and antibacterial agents. The antibacterial potency relates to infections or diseases caused by E. coli, S. typhi and S. aureus such as urinary tract infections, typhoid, diarrhea, skin diseases, and food poisoning. Pharmacological research on this genus is quite elementary and limited, thus, more advanced research is necessary to isolate and determine the activities of bioactive compounds in vitro and in vivo, establish their mechanisms of action and commence the process of clinical research.

Attenuation of cisplatin-induced emetogenesis by standardized Bacopa monnieri extracts in the pigeon: behavioral and neurochemical correlations.

Nausea and vomiting are the most distressing and common side effects of cancer chemotherapy which often result in patient noncompliance. In the present study, standardized methanolic and n-butanolic fractions of Bacopa monnieri were evaluated against cisplatin-induced emesis in the pigeon in relation to their activity on central and intestinal neurotransmitters levels. Cisplatin (7.0 mg/kg, i. v.) induced reproducible emesis without lethality in healthy pigeons. The methanolic (10-40 mg/kg) and the bacoside-rich n-butanolic fractions of B. monnieri (5-20 mg/kg), as well as the antioxidant N-(2-mercaptopropionyl) glycine (10 mg/kg), attenuated cisplatin-induced emesis by 66.3% (p < 0.05), 71.6% (p < 0.001), and 76.5% (p < 0.001), respectively, where the standard antiemetic metoclopramide (30 mg/kg) produced a 48.9% reduction (p < 0.01). The methanolic and n-butanolic fractions of B. monnieri at all of the doses tested significantly reduced the serotonin concentration (p < 0.001) in the brain stem and intestine 3 h after cisplatin administration, while at the 18th h, B. monnieri treatments attenuated not only the dopamine upsurge in the area postrema and brain stem (p < 0.05-0.001), but also the intestinal 5-HT concentration (p < 0.01-0.001). B. monnieri treatments alone did not alter the basal neurotransmitters or their metabolites in the brain areas and intestine. The prolonged suppressive effect of B. monnieri treatments on the behavioral signs of cisplatin-induced emesis, the subsequent supportive neural evidence, and the safety and tolerability profile suggest that B. monnieri methanolic and bacoside-rich n-butanolic fractions might be a valuable adjunct in the treatment of emetogenic chemotherapy, and this warrants further study in other models of emesis.

Effect of Bacopasides on acquisition and expression of morphine tolerance.

Opioids are extensively used for the management of both chronic malignant and non malignant pains. One major serious limitation associated with chronic use of opioids is the development of tolerance to its analgesic effect. The effect of Bacopa monnieri, a renowned ayurvedic medicine for acquisition and expression of morphine tolerance in mice, was investigated. Bacopa monnieri, n-Butanol fraction was analyzed on High performance liquid chromatography (HPLC), for Bacopaside A major components i.e. Bacoside A(3), Bacopaside ll and Bacosaponin C. Antinociceptive effect of n-Butanol extract of Bacopa monnieri (n Bt-ext BM) (5, 10 and 15 mg/kg) was assessed on hot plate. Effect of different doses of n Bt-ext BM on morphine antinociception was also assessed. n Bt-ext BM was also screened for development of tolerance to antinociceptive effect of Bacopa monnieri by administering 15 mg/kg n Bt-ext BM for seven days. Tolerance to morphine analgesia was induced in mice by administering intraperitoneally (I.P.) 20 mg/kg morphine twice daily for five days. Acute and Chronic administration of 5, 10 and 15 mg/kg n Bt-ext BM significantly reduced both expression and development of tolerance to morphine analgesia in mice. Additionally, Bacopa monnieri was found to enhance antinociceptive effect of morphine in intolerant animals. However, no tolerance to Bacopa monnieri antinociceptive effect was observed in seven days treatment schedule. These findings indicate effectiveness of Bacopa monnieri for management of morphine tolerance.